CN1113386A - Substituted kynurenines, a process for their preparation, and use as medicaments - Google Patents
Substituted kynurenines, a process for their preparation, and use as medicaments Download PDFInfo
- Publication number
- CN1113386A CN1113386A CN94190583A CN94190583A CN1113386A CN 1113386 A CN1113386 A CN 1113386A CN 94190583 A CN94190583 A CN 94190583A CN 94190583 A CN94190583 A CN 94190583A CN 1113386 A CN1113386 A CN 1113386A
- Authority
- CN
- China
- Prior art keywords
- amino
- compound
- formula
- phenyl
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000000034 method Methods 0.000 title claims description 32
- 238000002360 preparation method Methods 0.000 title claims description 10
- 239000003814 drug Substances 0.000 title description 4
- 230000008569 process Effects 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 108
- -1 phenyl-C1-C4 alkyl Chemical group 0.000 claims abstract description 41
- 108010068073 Kynurenine-oxoglutarate transaminase Proteins 0.000 claims abstract description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 20
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 17
- 239000003112 inhibitor Substances 0.000 claims abstract description 11
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 10
- 238000011282 treatment Methods 0.000 claims abstract description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 6
- 239000000203 mixture Substances 0.000 claims description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 20
- 150000002367 halogens Chemical group 0.000 claims description 16
- 238000006243 chemical reaction Methods 0.000 claims description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 230000003925 brain function Effects 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- VCCXKKFHLAJBJJ-UHFFFAOYSA-N 2-amino-4-(2-amino-5-chlorophenyl)-4-oxobutanoic acid Chemical compound OC(=O)C(N)CC(=O)C1=CC(Cl)=CC=C1N VCCXKKFHLAJBJJ-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 3
- XVTAZJDWEOGSAW-UHFFFAOYSA-N 2-amino-4-(2-amino-5-bromophenyl)-4-oxobutanoic acid Chemical compound OC(=O)C(N)CC(=O)C1=CC(Br)=CC=C1N XVTAZJDWEOGSAW-UHFFFAOYSA-N 0.000 claims description 3
- RBCCSNOOMUFUOM-UHFFFAOYSA-N 2-amino-4-(2-amino-5-cyclohexylphenyl)-4-oxobutanoic acid Chemical compound C1=C(N)C(C(=O)CC(N)C(O)=O)=CC(C2CCCCC2)=C1 RBCCSNOOMUFUOM-UHFFFAOYSA-N 0.000 claims description 3
- DQZFVWRQADFKMD-UHFFFAOYSA-N 2-amino-4-(2-amino-5-ethylphenyl)-4-oxobutanoic acid Chemical compound CCC1=CC=C(N)C(C(=O)CC(N)C(O)=O)=C1 DQZFVWRQADFKMD-UHFFFAOYSA-N 0.000 claims description 3
- JKNBLUQIGAJQQU-UHFFFAOYSA-N 2-amino-4-(2-amino-5-propan-2-ylphenyl)-4-oxobutanoic acid Chemical compound CC(C)C1=CC=C(N)C(C(=O)CC(N)C(O)=O)=C1 JKNBLUQIGAJQQU-UHFFFAOYSA-N 0.000 claims description 3
- POLYFBUWXSYRFD-UHFFFAOYSA-N 2-amino-4-(2-amino-5-propylphenyl)-4-oxobutanoic acid Chemical compound CCCC1=CC=C(N)C(C(=O)CC(N)C(O)=O)=C1 POLYFBUWXSYRFD-UHFFFAOYSA-N 0.000 claims description 3
- ODFJOVXVLFUVNQ-UHFFFAOYSA-N acetarsol Chemical compound CC(=O)NC1=CC([As](O)(O)=O)=CC=C1O ODFJOVXVLFUVNQ-UHFFFAOYSA-N 0.000 claims description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 2
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 abstract description 18
- 230000032683 aging Effects 0.000 abstract description 4
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 208000014644 Brain disease Diseases 0.000 abstract 1
- 125000000033 alkoxyamino group Chemical group 0.000 abstract 1
- 125000004104 aryloxy group Chemical group 0.000 abstract 1
- 208000010877 cognitive disease Diseases 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 230000009984 peri-natal effect Effects 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
- HCZHHEIFKROPDY-UHFFFAOYSA-N kynurenic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC(=O)C2=C1 HCZHHEIFKROPDY-UHFFFAOYSA-N 0.000 description 32
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 32
- 239000000243 solution Substances 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 29
- 238000003756 stirring Methods 0.000 description 16
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000000354 decomposition reaction Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 238000005406 washing Methods 0.000 description 10
- NHNUFAASKXPOQA-UHFFFAOYSA-N (3-acetamido-2-hydroxyphenyl)arsonic acid Chemical compound C(C)(=O)NC=1C(=C(C=CC1)[As](O)(=O)O)O NHNUFAASKXPOQA-UHFFFAOYSA-N 0.000 description 9
- KWOLFJPFCHCOCG-UHFFFAOYSA-N Acetophenone Natural products CC(=O)C1=CC=CC=C1 KWOLFJPFCHCOCG-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- LXJOYRVJPWDJBZ-UHFFFAOYSA-N (2-acetamido-3-hydroxyphenyl)arsonic acid Chemical compound OC=1C(=C(C=CC1)[As](O)(O)=O)NC(C)=O LXJOYRVJPWDJBZ-UHFFFAOYSA-N 0.000 description 8
- 102000004868 N-Methyl-D-Aspartate Receptors Human genes 0.000 description 8
- 108090001041 N-Methyl-D-Aspartate Receptors Proteins 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- VCCXKKFHLAJBJJ-MRVPVSSYSA-N (2r)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxobutanoic acid Chemical compound OC(=O)[C@H](N)CC(=O)C1=CC(Cl)=CC=C1N VCCXKKFHLAJBJJ-MRVPVSSYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 239000013543 active substance Substances 0.000 description 5
- 230000001476 alcoholic effect Effects 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000008101 lactose Substances 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 4
- 239000012299 nitrogen atmosphere Substances 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Substances OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- VCCXKKFHLAJBJJ-QMMMGPOBSA-N (2s)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxobutanoic acid Chemical compound OC(=O)[C@@H](N)CC(=O)C1=CC(Cl)=CC=C1N VCCXKKFHLAJBJJ-QMMMGPOBSA-N 0.000 description 3
- RQEUFEKYXDPUSK-UHFFFAOYSA-N 1-phenylethylamine Chemical compound CC(N)C1=CC=CC=C1 RQEUFEKYXDPUSK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 241001529936 Murinae Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
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- 239000003999 initiator Substances 0.000 description 3
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- 229940032147 starch Drugs 0.000 description 3
- UIUJIQZEACWQSV-UHFFFAOYSA-N succinic semialdehyde Chemical compound OC(=O)CCC=O UIUJIQZEACWQSV-UHFFFAOYSA-N 0.000 description 3
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- WRMNZCZEMHIOCP-UHFFFAOYSA-N 2-Phenylethanol Natural products OCCC1=CC=CC=C1 WRMNZCZEMHIOCP-UHFFFAOYSA-N 0.000 description 2
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 description 2
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- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
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- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
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- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
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- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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Abstract
The present invention relates to the use in the treatment of cognitive disorders associated with the aging processes of the brain and perinatal brain disorders of compounds which act as inhibitors of the enzyme kynurenine aminotransferase (KAT). The present invention also provides, as novel compounds, a selected class of KAT inhibitors which are the compounds of formula (IA) wherein R is halogen, C1-C6 alkyl, C5-C7 cycloalkyl, phenyl-C1-C4 alkyl, C1-C6 alkoxy, C6-C10 aryloxy, phenyl-C1-C4 alkoxy or trifluoromethyl, and R1 is hydroxy, C1-C6 alkoxy, amino, mono-C1-C6 alkylamino, di-C1-C6 alkylamino, hydroxylamino, C1-C4 alkoxyamino or benzyloxyamino.
Description
The present invention relates to new medical use and some new compounds of some compound, and the method and the pharmaceutical composition that contains these compounds that prepare these compounds.
Especially, the present invention relates to be used for the treatment of the compound that obstacle is known in the knowledge relevant with the brain aging process, this compounds is used as the kynurenine aminotransferase inhibitor of (being called KAT in the prior art).
These compounds as the KAT inhibitor can be identified by standard test, for example according to J.Neurochem., 57,533-540(1991), in the homogenate of murine brain, measure compound to suppressing the active ability of KAT, perhaps according to J.Neurochem., 52,1629-1636(1989) restraining effect that this compounds generates kynurenic acid (KYNA) is measured in the murine brain section that utilizes described in.
The catalysis of KAT energy is turned to the biosynthesizing of KYNA by kynurenine (KYN):
And KAT is the special material (J.Neurochem., 57,533-540,1991) of replying that the KYNA EC is regulated in the brain.
KYNA is effective excited amino acid (EAA) receptor antagonist, and it has extra high affinity (J.Neurochem., 52,1319-1328,1989) to the glycine regulatory site of N-methyl-D-aspartate (NMDA) receptor complex.
As naturally occurring brain meta-bolites (J.Neurochem., 51,177-180,1988 and Brain Res, 454,164-169,1988), KYNA may be as the reverse endogenous conditioning agent of brain L-glutamic acid function and work (Ann.N.Y.Acad.Sci., Vol.648, P.140-153,1992).
The EAA acceptor, particularly nmda receptor is known, its (J.C.Watkins and G.L. that in mammal brain, plays an important role, Collingridge-edits-, The NMDA receptor, Oxford University Press, Oxford, 1989, PP.242).For example, the activation of nmda receptor is to cognitive process, and for example learning and memory is important (J.C.Watkins and G.L.Collingridge-eds-, In:The NMDA receptor, Oxford University Press, Oxford, P.137~151,1989), it also is important (Trends Pharmacol.Sci. that brain is evolved, 11,290~296,1990).
Therefore, the decline of nmda receptor function is to the brain physiological function, and then whole organism is had adverse influence.The minimizing of the nmda receptor quantity that for example occurs in the brain of aging (Synapse, 6,388~343,1990) may the knowledge relevant with aging be known what the imbalance of function was associated.
In brain, the activity of the biosynthetic enzyme KAT of the concentration of KYNA and KYNA rise appreciably with age (Brain Res.558,1~5,1992 and Neurosci, Lett., 94,145~150,1988).The KAT inhibitor is by making the segmental increase of L-glutamic acid on the nmda receptor, to nmda receptor function insufficient and/or KAT is active and KYNA to measure unusual enhanced situation particularly useful.Therefore, they are to treatment and old and feeble relevant pathological manifestations, and for example, obstacle is known in the elderly's knowledge, comprises that attention and memory weaken and the phenomenon of having a sleepless night is particularly useful.
The KAT inhibitor also can be used for the treatment of brain function imbalance in term, brain function imbalance in term may with irregular relevant (the H.Baran and R.Schwarcz:Regional differences in the ontogenic pattern of KAT in the rat brain in the special type of characteristic area that postpartum, KAT evolved, Dev.Brain Res., in press).
Therefore a first aspect of the present invention comprises the application of KAT inhibitor aspect treatment brain function imbalance in term.
In specification sheets of the present invention, " treatment " speech comprises that " prophylactic treatment " reaches " obviously alleviating of symptom ".
According to the present invention, the specific compound that is used as the KAT inhibitor is that the 5-with following logical formula I replaces the kynurenine derivative:
Wherein R is halogen, C
1-C
6Alkyl, C
5-C
7Cycloalkyl, phenyl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, phenyl C
1-C
4Alkoxyl group or trifluoromethyl;
R
1Be hydroxyl, C
1-C
6Alkoxyl group, amino, list-C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, hydroxyl amino, C
1-C
4Alkoxy amino or benzyloxy amino.
The present invention also comprises the acceptable salt of medicine as the formula I compound of KAT inhibitor, and the possible isomer of the Individual existence of formula I representative or mixing existence.
The present invention also relates to some new compound of formula I compound representative.
As the compound of second purpose of the present invention, be compound with following general formula (IA):
Wherein R is halogen, C
1-C
6Alkyl, C
5-C
7Cycloalkyl, phenyl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, phenyl C
1-C
4Alkoxyl group or trifluoromethyl;
R
1Be hydroxyl, C
1-C
6Alkoxyl group, amino, list-C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, hydroxyl amino, C
1-C
4Alkoxy amino or benzyloxy amino.
Condition is:
(ⅰ) work as R
1Be that then this halogen was not a fluorine when hydroxyl and while, R was halogen; With
(ⅱ) work as R
1Be that hydroxyl and while R are C
1-C
6During alkyl, this C then
1-C
6Alkyl is not a methyl.
The medicinal acceptable salt that also comprises formula (IA) compound in second purpose of the present invention reaches the Individual existence of formula (IA) representative or mixes the whole possible isomer that exists, and is subjected to the restriction of above-mentioned condition equally.
In this manual, for above-mentioned formula I and (IA), various substituent features are as follows:
" halogen " represents Cl, Br, I or F, preferred Cl and Br.
" C
1-C
6Alkyl " comprise for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl and n-hexyl, preferably methyl, ethyl, n-propyl or sec.-propyl.
" C
5-C
7Cycloalkyl " represent the monocyclic carbocyclic ring of 5~7 joints, preferably cyclopentyl or cyclohexyl.
" C
6-C
10Aryloxy " comprise for example phenoxy group and naphthyloxy; Phenoxy group preferably.
" phenyl-C
1-C
4Alkyl " representative contains the C of phenyl
1-C
4Alkyl, for example benzyl or 1-phenylethyl; Benzyl preferably.
" phenyl-C
1-C
4Alkoxyl group " representative contains the C of phenyl
1-C
4Alkoxyl group, for example benzyloxy or 1-phenyl ethoxy; Benzyloxy preferably.
" C
1-C
6Alkoxyl group " comprise, for example, methoxyl group, oxyethyl group, positive propoxy and isopropoxy; Methoxy or ethoxy preferably.
" C
1-C
6Alkylamino " comprise, for example, methylamino-, ethylamino, n-propylamine base, isopropylamino and n-butyl amine base; Methylamino-preferably.
" C
1-C
4Alkoxy amino " comprise, for example, methoxy amino, ethoxy amino, positive third oxygen amino and the different third oxygen amino; Methoxy amino preferably.
Formula I and (IA) compound have a unsymmetrical carbon, thereby they may exist with racemic mixture (enantiomorph) form of optical isomer, or exist with single optical isomer form.
Except as otherwise noted, formula I or (IA) the S configuration of the asymmetric center of compound be equivalent to the L type of natural kynurenine, otherwise the R configuration is equivalent to the D type of natural kynurenine.
Formula I or (IA) the medicinal acceptable salt of compound comprise and use the formed salt of medicinal acceptable acids, or mineral acid, for example hydrochloric acid, Hydrogen bromide, nitric acid or sulfuric acid or organic acid, for example citric acid, tartrate, toxilic acid, fumaric acid, methylsulfonic acid or ethyl sulfonic acid, perhaps, when formula I or compound (IA) contain acidic-group, for example during carbonyl, then form salt, for example basic metal with medicinal acceptable alkali, as sodium or potassium, alkaline-earth metal such as calcium or magnesium; Zinc or aluminium; Or for example aliphatic amine of organic bases such as methylamine, diethylamine, Trimethylamine, ethamine and heterocyclic amine such as pyridine.
The preferred compounds of the present invention is the compound by formula (IA) expression, its single isomer or isomer mixture, and medicinal acceptable salt, and wherein R is a halogen, C
1-C
6Alkyl or C
5-C
7Cycloalkyl; R
1It is hydroxyl; Condition is:
(ⅰ) when R is halogen, then this halogen is a fluorine not; With
(ⅱ) when R be C
1-C
6During alkyl, this C then
1-C
6Alkyl is not a methyl.
The special case of the preferred compound of above-mentioned formula (IA) has:
2-amino-4-(2-amino-5-chloro-phenyl-)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-ethylphenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-bromophenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-n-propyl phenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-isopropyl phenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-cyclohexyl phenyl)-4-oxo-butyric acid;
And the single isomer of above-claimed cpd or mixture of isomers and medicinal acceptable salt thereof.
Formula I of the present invention or compound (IA) can prepare according to following method:
1) makes the compound of formula II and chloro acetonitrile reaction and obtain the compound of formula III
Wherein R such as formula I or (IA) in definition,
Wherein the R definition as above.
2) compound of formula III and the sodium salt of diethyl kharophen propanedioic acid are reacted, obtain the compound of formula IV
Wherein the R definition as above.
3) compound of formula IV is handled with concentrated hydrochloric acid, obtained R and define as above and R
1Be the formula I of hydroxyl or compound (IA); If desired, can convert formula I or compound (IA) to R
1Part is not the another kind of formula I of hydroxyl or compound (IA); And if desired, can be with formula I or compound salify (IA); And if desired, can with formula I or (IA) isomer mixture of compound be separated into single isomer.
Perhaps, formula I or compound (IA) can directly obtain single isomer by Stereoselective ground directional synthesis method.
The compound and the reaction between the chloromethyl cyanide of formula II can be finished by following steps, in the dichloromethane solution of the boron trichloride that is stirring, add the solution of formula II compound in dry-out benzene, add chloro acetonitrile and aluminum chloride then, the mixture of gained was refluxed 20 hours.
Reaction between the compound of formula III and the kharophen propanedioic acid sodium salt can be undertaken by following step: add acetamino diethyl malonate (being dissolved in the ethanol) in the alcoholic acid sodium solution, the compound that adds formula III then, reaction mixture was placed 20 hours, then in 40 ℃ of heating 4 hours in room temperature.
The compound of formula IV and the reaction between the concentrated hydrochloric acid for example can be carried out as follows: the compound of formula IV was refluxed in concentrated hydrochloric acid 7 hours.
R wherein
1Not the formula I of hydroxyl or compound (IA), the method that can know altogether according to those of ordinary skill in the art, by R as defined above and R
1The formula I of hydroxyl or compound (IA) are made initiator and are prepared.
Formula I or compound salify (IA) can be carried out in accordance with known methods; Normally implement by compound of the present invention and an amount of salt-forming reagent reacted.
As above-mentioned, in formula I or the compound (IA) unsymmetrical carbon is arranged, so these compounds can exist with the racemization mixed form, also may exist with single optical isomer (diastereomer) form.Thereby these compounds can synthesize as the form of mixture earlier, by ordinary method desired isomer separation are come out then, or synthesize by known steroselectivity method.
Being separated into single optical isomer from corresponding racemic mixture for example can carry out as follows: according to method well known in the prior art; use suitable amino acid blocking group; as ethanoyl, carbonyl carbobenzoxy-(Cbz) or tertbutyloxycarbonyl, with racemic formula I or (IA) compound convert the compound of N-protected to.Then with the derivative of the N-protected of the racemic compound of resulting formula I or formula (IA); with suitable optically active amines such as Alpha-Methyl benzylamine; brucine or cinchonine; behind salify in the presence of appropriate solvent such as the ethyl acetate Huo diox; carry out recrystallization again; obtain the formula I or (IA) salt of the pure diastereomer of a kind of mapping of compound; use the currently known methods deprotection then, and obtain formula I or (IA) (R) that take apart or (S) enantiomorph of compound.
Perhaps also can directly obtain the formula I or (IA) single enantiomer of compound by Stereoselective ground directional synthesis method.
For example, with the compound of formula (V),
(wherein R is halogen, C
1-C
6Alkyl, C
5-C
7Cycloalkyl, phenyl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, phenyl-C
1-C
4Alkoxyl group or trifluoromethyl;
R
2Be COR
3Or COOR
3, R wherein
3Be C
1-C
6Alkyl)
React with formula (VIA) or compound (VIB),
(R wherein
2By defining in formula (V) compound) then the compound of gained is hydrolyzed with suitable hydrolytic reagent such as HCl or HBr, obtain wherein R as defined above and R
1Be the formula I of hydroxyl or (IA) the pure enantiomorph of compound.
By standard operation well known to those skilled in the art, can be with R
1Be the formula I of hydroxyl or (IA) the pure enantiomorph of compound convert substituent R to
1Be the formula I of hydroxyl or another kind of compound (IA).
Formula (V) compound and formula (VIA) or (VIB) reaction between the compound for example can finish by following method, (in the presence of dibenzalacetone two palladiums (O)-chloroform adducts, reactant mixed and carry out as three at suitable palladium mixture.
The compound of formula (V) can be by the known method preparation of prior art (J.Org.Chem.1979,44,1133).
Formula (VIA) or compound (VIB) can be by prior art currently known methods preparations (J.Org.Chem.1988,53,6138).
C in formula (VIA) or the compound (VIB)
1-C
6The connotation of alkyl and formula I or (IA) identical in the compound.
Perhaps, also can directly obtain the enantiomorph of compound pure formula I or (IA), for example, by with formula I or racemic compound (IA) or and response derivative, with suitable optically pure amine, as (R)-(-)-or (S)-(+)-2-amino-2 phenylethyl alcohol, in appropriate solvent such as dimethyl formamide (DMF) as react under 5 ° to 25 ℃ temperature, the reaction times can be as between 1 hour to 48 hours.Resulting diastereomer can obtain pure epimer (being only conformation difference on an asymmetric center of diastereomer) by the chromatography separation, this product is hydrolyzed through suitable hydrolytic reagent such as HCl or HBr, and obtains the compound of formula I or enantiomer-pure (IA).
In compound of the present invention synthetic, be the compound that can be purchased as the aniline of the replacement that is equivalent to the formula II compound of initiator, or be prepared by method well known to those skilled in the art.
Formula I or compound (IA) can be with following test A in the efficient that suppresses kynurenine aminotransferase (KAT)), B), C) show.
A) the active mensuration that suppresses of KAT in the murine brain homogenate
KAT measures (Measurement of rat brain kynurenine amino-transferase at physiological kynurenine concenrtrations with the method that OKuno et al. describes in detail, J.Neurochem., 57,533-540,1991).In brief, animal is by sacrificed by decapitation, then with the cerebral tissue homogenize (1:5v/w is at 5mMTris-acetic ester damping fluid, among the pH8.0, contain 10mM2-mercaptoethanol and 50 μ m pyridoxals-5 '-phosphoric acid) and at 2 μ m[
3H] KYN(30 n Ci), 1mM2-ketoisocaproic and 70 μ M pyridoxals-5 '-the phosphoric acid existence is following, in 150nMTris-acetic ester pH of buffer 8.0, cultivated 2 hours in 37 ℃.This reaction stops by adding trichoroacetic acid(TCA).
New synthetic [
3H] KYNA on Dowex 50 W cationic exchange coloums by [
3H] separate among the KYN, and quantitative with the liquid scintillation Zymography.10 minutes tissue of heated and inactivated has carried out blank in boiling water by using.
When testing under these conditions, compound of the present invention can suppress the activity of KAT.
With formula I that can the representative amount or (IA) compound and the results are shown in the following table of obtaining:
Table 1
Nc=does not calculate
B) measure the inhibition that KYNA is produced by the rat tissue section
According to routine, the section (1 * 1mm that obtains from pallium; Heavy ≈ 1.5mg/ sheet) separating on ice, changes over to then (10/ware) in the culture dish, contain Krebs-Ringer damping fluid (NaCl, the 118.5mM of the oxidation of 1ml in this culture dish; KCl, 4.75mM; CaCl
2, 1.77mM; MgSO
4, 1.18mM; NaH
2PO
4, 12.9mM; NaH
2PO
4, 3mM; Glucose, 5mM; PH7.4).Then, in the presence of 50 μ M L-KYN, in the water-bath of jolting, this is organized in 37 ℃ of pre-down cultivations 10 minutes, cultivates 2 hours at 37 ℃ then again in oxygen room.As requested, compound of the present invention is included in the culture.After the cultivation, rapidly culture dish is placed on ice, will cut into slices apace and separate with substratum.In order to measure KYNA, the media samples of 1ml be impregnated in the boiling water bath 10 minutes, centrifugal then (8.730 * g, 10 minutes) remove sedimentary protein.(1:1 v/v), and is added to Dowex 50 W(Hydrogens to supernatant liquor, and Sigma) cationic exchange coloum is (on 0.5 * 2cm) with 0.2M HCl dilution.Then, with the 0.1M HCl of 1ml and this post of water washing of 1ml, the part that contains KYNA is come out with the water elution of 2ml.Elutriant is added to 3-μ m C
18The HPLC post (100 * 3.2 internal diameters, Bioanalytical Systems, West Lafayette, IN, U.S.A), KYNA is with containing the speed wash-out of the moving phase of 50mM ammonium acetate and 5% methyl alcohol with 0.5ml/min, and under this condition, ≈ is 7 minutes during the reservation of KYNA.
Record data and be connected to the 160UV that places 340nm absorb monitor (Beckman Instruments, Berkeley, CA, Hewlett-Packard 3390A totalizing instrument U.S.A) calculates.
In this test, tested with formula I or compound (IA) that code name is represented, the results are shown in Table 2 for gained.
Table 2
*Do not calculate at 300 μ m nc=
Used abbreviation in table 1 and the table 2: Me, Et, n-Pr, i-Pr be represent methylidene, ethyl, n-propyl and sec.-propyl respectively.
C) use the partial purification zymin carry out dynamic analysis KAT inhibitor (Brain Research, 534,37-44(1990).
In the reaction mixture of 0.1ml cumulative volume, contain useful unlabelled KYN be diluted to ultimate density be 2 μ m [
3H] KYN(30 nCi), 1mM pyruvate salt, 70 μ m pyridoxals-5 '-phosphoric acid, 150mM Tris-acetate buffer pH8.0 and partially purified zymin.If desired, test-compound is included in the culturing mixt, and this reaction begins by adding pyruvate salt, at 37 ℃ of 50%(w/w that add 14 μ l after cultivating 2 hours) trichoroacetic acid(TCA) and make reaction terminating.Then, add the 0.1M HCl of 1ml, and metaprotein is removed with centrifugal 4 minutes of Beckman52B microcentrifuge.The supernatant liquor of the gained of 1ml is added in Dowex 50 W post (0.5 * 1.0cm; H
+Type) on,, uses the distilled water wash of 1ml then earlier with the 0.1M HCl washing of 1ml.[
3H] the KYNA distilled water wash-out of 2ml, and quantitative with liquid phase scintillation spectrum analytical method.The enzymatic determination triplicate, blank is by 10 minutes zymin of heated and inactivated is carried out in boiling water bath.
Dynamic test is to use above-mentioned standard K AT method, and under the condition that exists at the test-compound that is with or without fixed concentration, the concentration that changes the KYN between 2 μ m to 2mM is carried out.With twice multiple point mapping, determine best curve by linear regression analysis.
Kinetic constant:
L-kynurenine D, L-5-Cl, kynurenine
Km Ki
369μM 88μM
The present invention also comprises some pharmaceutical compositions in its scope, any possible isomer and mixture of isomers that said composition contains the active substance of the formula I for the treatment of significant quantity or compound (IA) or its medicinal acceptable salt and formula I or (IA) comprises, one or more medicinal acceptable carriers, thinner or vehicle that it is relevant.
Mammals as the people, is that available medicinal compositions of the present invention is treated.
Compound of the present invention can pass through conventional route, parenteral admin for example, as by intravenous injection or transfusion, intramuscularly, subcutaneous, partial or oral or other pass through the suitable form administration that sucks or be blown into.Dosage depends on patient's age, body weight and condition, the effectiveness of compound and route of administration.For example, for the grownup, active matter quality was 0.1 to 100mg during suitable application dosage was every dose, took every day 1~4 time.Medicinal compositions of the present invention prepares as follows usually and uses with medicinal acceptable form.For example the solution of intravenous injection or the transfusion carrier that can contain is a sterilized water, or the salt brine solution of preferably aseptic isotonicity.
The suspension agent of intramuscularly, solution or emulsion can contain: with the medicinal acceptable carrier of active compound, for example, sterilized water, sweet oil, ethyl oleate, dibasic alcohol such as propylene glycol and an amount of if necessary lidocaine hydrochloride.
Can contain other pharmaceutical formulation such as suspending agent, stablizer and/or dispersion agent in the prescription of injection.
Perhaps, activeconstituents can be with Powdered preparation, before use with suitable carriers such as aseptic pyrogen-free water and constitute.In the topical application preparation, during as creme, lotion, paste, activeconstituents can mix with butyraceous or emulsive carrier commonly used.
Solid orally ingestible as tablet and capsule, can contain with active substance: thinner, for example lactose, glucose, sucrose, Mierocrystalline cellulose, W-Gum and potato starch; Lubricant is silica, talcum powder, stearic acid, Magnesium Stearate or calcium for example, and/or polyoxyethylene glycol; Wedding agent, for example, starch, gum arabic, gelatin, methylcellulose gum, carboxymethyl cellulose, polyvinylpyrrolidone; Depolymerizing agent, for example starch, alginic acid, alginate, sodium starch glycol; Effervescent mixture; Tinting material; Sweeting agent; Wetting agent, for example Yelkin TTS, Spheron MD 30/70, laurilsulfate; And, common inert material on employed nontoxic, the medicine in the pharmaceutical preparation.Described pharmaceutical preparation can be prepared according to currently known methods, for example by methods such as mixing, granulation, compressing tablet, sugar coating or coatings.
Tablet is also to carry out dressing with methods known in the art.
The preparation of liquid oral form, for example, suspensoid, syrup or liquor can be according to a conventional method, for example, with medicinal acceptable additive, sanitas, sweeting agent/or seasonings and preparing.
Medicinal compositions of the present invention can be made some formulation by method well known in the art, make this medicinal compositions be applied to the patient after, its activeconstituents can or fast or continue or discharge lentamente.
Following embodiment but does not limit the present invention in order to explanation the present invention.
Embodiment 1
5-chloro-2 amino-alpha-chloro phenyl methyl ketone
Under nitrogen atmosphere, temperature is that (100ml 1M drips 4-chloroaniline (12.12g, dry-out benzene solution (120ml) 0.095mol) in 0.1mol) to the dichloromethane solution of the boron trichloride that is stirring under 5 ℃ to 10 ℃ the condition.
In the mixture of gained, add successively the chloro acetonitrile (7.72ml, 0.115mol) and aluminum chloride (13.33g, 0.1mol).Then, this mixture was refluxed 20 hours.
After the cooling, add ice-cooled 2N hydrochloric acid (≈ 100ml), form a kind of yellow mercury oxide, mixture is under agitation in 80 ℃ of heating, up to resolution of precipitate (≈ 45 ').
Cooled solution makes pH transfer to 2 by adding 2N NaOH, and with dichloromethane extraction (three times).
Organic phase washes with water, dry then (Na
2SO
4), and concentrate.
Residue grinds with hexane (≈ 120ml), obtains the required light brown solid product of 9.27g, m.p.133-136 ℃.
According to similarity method, can make following compounds:
5-methyl-2-amino-alpha-chloro phenyl methyl ketone, m.p.127~129 ℃;
5-fluoro-2-amino-alpha-chloro phenyl methyl ketone, m.p.121~123 ℃;
5-ethyl-2-amino-alpha-chloro phenyl methyl ketone, m.p.118~120 ℃;
5-cyclohexyl-2-amino-alpha-chloro phenyl methyl ketone, m.p.88~91 ℃;
5-bromo-2-amino-alpha-chloro phenyl methyl ketone, m.p.127~130 ℃;
5-n-propyl-2-amino-alpha-chloro phenyl methyl ketone, m.p.119~122 ℃;
5-sec.-propyl-2-amino-alpha-chloro phenyl methyl ketone, m.p.66~70 ℃.
Embodiment 2
Acetylaminohydroxyphenylarsonic acid (2-amino-5-chlorobenzoyl methyl) malonic ester
(1.04g 0.0453mol) is dissolved in the ethanol (80ml), and (9.84g, 0.0453mol) at 120ml alcoholic acid solution, this solution was 45 ℃ of heating 1 hour to add acetamino diethyl malonate with sodium.
After being cooled to room temperature, (9.25g 0.0453mol) at 150ml alcoholic acid solution, stirs under nitrogen atmosphere simultaneously Dropwise 5-chloro-2-amino-alpha-chloro phenyl methyl ketone.
With reactant stirring at room 20 hours, then with this mixture 40 ℃ of heating 4 hours.Reaction mixture is evaporated to dried, residue 300ml water dissolution, and add 1N NaOH(20ml), use extracted with diethyl ether.
Organic phase washes with water, and is dry and be evaporated to driedly, obtains solid, obtains the required paste solid product of 6.02g with 210ml Virahol recrystallization, m.p.156~158 ℃.
According to similar methods, can prepare following compounds:
Acetylaminohydroxyphenylarsonic acid (2-amino-5-toluyl methyl)-diethyl malonate, m.p.179~181 ℃;
Acetylaminohydroxyphenylarsonic acid (2-amino-5-fluoro phenacyl)-diethyl malonate, m.p.143~145 ℃;
Acetylaminohydroxyphenylarsonic acid (2-amino-5-ethylbenzoyl methyl)-diethyl malonate, m.p.121~123 ℃;
Acetylaminohydroxyphenylarsonic acid (2-amino-5-cyclohexyl phenacyl)-diethyl malonate, m.p.89~93 ℃;
Acetylaminohydroxyphenylarsonic acid (2-amino-5-bromo phenacyl)-diethyl malonate, m.p.151~154 ℃;
Acetylaminohydroxyphenylarsonic acid (2-amino-5-n-propyl phenacyl)-diethyl malonate, m.p.115~117 ℃; With
Acetylaminohydroxyphenylarsonic acid (2-amino-5-sec.-propyl phenacyl)-diethyl malonate, m.p.110~115 ℃.
Embodiment 3
2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (D, L-5-chloro-kynurenine)
(5.3g, 0.01377mol) solution at concentrated hydrochloric acid (60ml) refluxed 7 hours with acetylaminohydroxyphenylarsonic acid (2-amino-5-chloro phenacyl) diethyl malonate under stirring.
Reactant vacuum-evaporation is to doing, and the residue water dissolution is used washed with dichloromethane.
Water is concentrated, in the residue water-soluble (100ml), gained solution is transferred to 6.5 and obtain required yellow mercury oxide product with 2N NaOH with pH.
Filter, the washing solid obtains the required product of 3.10g, m.p.236~238 ℃ (decomposition).
According to similar method, can prepare following compounds:
2-amino-4-(2-amino-5-aminomethyl phenyl)-4-oxo-butyric acid, m.p.230~250 ℃ (decomposition);
2-amino-4-(2-amino-5-fluoro phenyl)-4-oxo-butyric acid, m.p.200~225 ℃ (decomposition);
2-amino-4-(2-amino-5-ethylphenyl)-4-oxo-butyric acid, m.p.210 ℃ (decomposition);
2-amino-4-(2-amino-5-cyclohexyl phenyl)-4-oxo-butyric acid, m.p.230~250 ℃ (decomposition);
2-amino-4-(2-amino-5-bromo phenyl)-4-oxo-butyric acid, m.p.233 ℃ (decomposition);
2-amino-4-(2-amino-5-n-propyl phenyl)-4-oxo-butyric acid, m.p.233~234 ℃ (decomposition);
2-amino-4-(2-amino-5-isopropyl phenyl)-4-oxo-butyric acid, m.p.235 ℃ (decomposition).
Embodiment 4
The method of taking apart by diastereomeric salt prepares (S) (-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (L-5-chloro kynurenine) and
(R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (D-5-chloro kynurenine)
To the 2-amino that is stirring-4-(2-amino-5-chlorophenyl)-the 4-ketobutyric acid (5.23g, 21.55mmol), NaHCO
3(3.98g, 47.4mmol) and Na
2CO
310H
2O(6.16g, 21.55mmol) in the solution of 300ml water, drip under the room temperature diacetyl oxide (2.236ml, 23.7mmol).
With solution stirring 1 hour, be acidified to pH5 with 2N HCl, with ethyl acetate extraction (4 times), washing, dry and evaporation is to obtain a light yellow solid.
This crude product grinds with hexane, obtains 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-4-ketobutyric acid (4.20g; 68.4%; M.p.187-190 ℃).
To the 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl that stirs)-4-ketobutyric acid (4.20g 14.75mmol) in 500ml95% alcoholic acid solution, drips R-(+)-Alpha-Methyl benzylamine (1.88ml, 14.75mmol).After 20 minutes, solvent evaporation is fallen, residue obtains solids (5.10g with the ether development; M.p.130~150 ℃; [α]
20 D=+2.5 ° (1%, CH
3OH).
With re-crystallizing in ethyl acetate four times, obtain 1.12g(enantiomorph yield 37%) 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-salt of 4-oxo-butyro-(-)-Alpha-Methyl benzylamine (m.p.154.5~156 ℃; [α]
20 D=-60.8 ° (1%, CH
3OH).
(1.12g 2.76mmol) in the solution of ethyl acetate (100ml), adds entry (20ml) and 1N HCl(2.9ml, 2.9mmol) to (-)-Alpha-Methyl benzylamine salt of vigorous stirring.After 30 minutes, tell organic phase, the water ethyl acetate extraction.The organic phase that merges washes with water, dry and evaporation and obtain light brown (-)-2-alpha-acetamido--4-(2-amino-5-chlorophenyl)-4-ketobutyric acid (0.76g; 97%) solid (m.p.182~183.5 ℃ (decomposition); [α]
20 D=-88.7 ° (1%, CH
3OH).
With (-)-2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-solution in 4-oxo-butyric acid (0.76g is 2.67mmol) at 2N HCl(90ml), heating is 3 hours under reflux temperature, and this aqueous solution evaporate is to doing, soluble in water with residue, uses CH
2Cl
2Washing and revaporization.With transferring pH to 6.5 in the residue water-soluble (30ml) and with 1N NaOH, separate out the faint yellow solid thing.This solid filtering is also used cold water washing, obtains (R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (0.40g; 59.7%; M.p.210~211 ℃ (decomposition); [α]
20 D=+11.5(1%, CH
3COOH; Ee=96%).
To prepare (-)-Alpha-Methyl benzylamine salt process in the mother liquor of gained mix and evaporation, obtain 4.9g(12mmol) solid.Mixture and 400ml ethyl acetate that should (-) and (+) salt, 80ml water and 1N HCl(12.6ml, 12.6mmol) vigorous stirring together.After 30 minutes, tell organic phase, the water ethyl acetate extraction.The organic phase that merges washes with water, and drying is also evaporated, and is rich in the 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl of (+) enantiomorph)-4-oxo-butyric acid (light brown solid) (3.41g; 100%; M.p.172~178 ℃).
To the 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl that is stirring)-4-oxo-butyric acid (3.41g, 11.97mmol) in 400ml95% alcoholic acid solution, dropping (S)-(-)-Alpha-Methyl benzylamine (1.52ml, 11.97mmol).After 20 minutes, solvent evaporated.Carry out obtaining 1.49g(61.3% behind three recrystallizations with ethyl acetate) 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-4-oxo-butyro-(+)-Alpha-Methyl benzylamine salt (m.p.154.5~155.5 ℃); [α]
20 D=+60.9(1%, CH
3OH).
1.49g above-mentioned salt by above-mentioned, the method that is used for prepare (-) enantiomorph is carried out, and obtains 1.03g(98.5%) (+)-2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (m.p.179~180 ℃, decomposition); [α]
20 D=+89.0(1%, CH
3OH).
In order to prepare (R) enantiomorph, use as stated above (+)-2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid makes initiator, obtains 0.65g(71.4%) (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (m.p.208~209 ℃ (decomposition); [α]
20 D=-12.6 ° (1%, CH
3COOH, ee=96%).
Embodiment 5
Select synthetic method preparation (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl by enantiomorph)-4-oxo-butyric acid (L-5 chloro kynurenine) and (R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (D-5-chloro kynurenine).
Under nitrogen atmosphere, with ice bath cooling 4-chloro-N-pivalyl aniline (2.11g, 10mmol) solution in the 30ml anhydrous tetrahydro furan.Drip then 1.6M n-Butyl Lithium (15.625ml, hexane solution 25mmol), 0 ℃ stir 2.5 hours after, (2.19g 11mmol) is dissolved in the solution of anhydrous tetrahydro furan (8ml) to add the chlorination trimethyl tin in 0 ℃ in 20 minutes.Then this reactant was stirred 2 hours at 0 ℃, in stirring at room 16 hours, water quenching, and use the salt water washing of ethyl acetate extraction, organic phase, drying also is concentrated into dried.Residue on silicagel column with sudden strain of a muscle formula chromatography purification (diisopropyl ether: 40 °/70 ° of sherwood oils=10:23), obtain the white solid of 3.1g4-chloro-2-trimethylammonium stannyl-N-pivalyl aniline, (82.9%, m.p.169~172 ℃).
*Joc44,1133(1979)
With 4-chloro-2-trimethylammonium stannyl-N-valeryl aniline (1.6g, 4.2mmol) and (S)-(1.25g 42mmol) is dissolved in the dry toluene (50ml) 3-carbobenzoxy-(Cbz)-5-oxo-4-oxazolidine Acetyl Chloride 98Min..In this solution, add Pd
2(dba)
3CHCl
3(40.5mg), this mixture was 70 ℃ of heating 8 hours.After the mixture cooling, remove catalyzer by diatomite filtration, filtrate concentrates, and dilutes with ethyl acetate then; The solution of gained is successively with saturated supercarbonate, water and saturated NaCl washing, dry then and evaporation.Residue on silicagel column with sudden strain of a muscle formula chromatography purification (ethyl acetate: hexane=8:30), obtain (S)-(+)-N-pivalyl-2-[1-oxygen-2-[3-(carbobenzoxy-(Cbz))-5-oxo-oxazolidines-4-yl]-ethyl]-the clear crystal 1.06g(53.5% of 4-chloroaniline); M.p.113~116 ℃; [α]
20 D=-114.5(1%, ethyl acetate).
*JOC53,6138(1988)。
With (S)-(+)-N-pivalyl-2-[1-oxygen-2-[3-(carbobenzoxy-(Cbz) that is stirring)-5-oxygen-oxazolidines-4-yl] ethyl]-4-chloro aminobenzen (1.06g, 2.24mmol), 37%HCl(20ml), H
2O(20ml) and CH
3COOH(28ml) mixture to doing, in the residue water-soluble (30ml), is used CH with this solution evaporation in 70 ℃ of heating 5.5 hours
2Cl
2Sudden strain of a muscle formula chromatography purification (chloroform: methyl alcohol: 30%NH is used in washing and evaporation once more, crude product on silicagel column
4OH=140:60:6), obtain (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyro-yellow crystal (0.29g; 51.5%; M.p.206~208 ℃; [α]
20 D=-12.0 ° (1%; CH
3COOH); Ee=96%).
By similar approach, can prepare:
(R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (D-5-chloro kynurenine); [α]
20 D=+11.5 ° (1%, CH
3COOH).
Embodiment 6
Formation by diastereomer and chromatographic separation preparation (S)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (L-5-chloro kynurenine) and (R)-(+)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid (D-5-chloro kynurenine).
Under the nitrogen atmosphere, in the time of 5~8 ℃, to the 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl-4-oxo-butyric acid (0.569g that is stirring; 2mmol) at no DMF(8ml) solution in, add 1,1 in batches '-carbonyl dimidazoles (0.34g; 2.1mmol).After 1.5 hours, in the time of 3~5 ℃, drip the 2-of (R)-(-) amino-2 phenylethyl alcohol (0.33g 5 ℃ of stirrings; 2.4mmol) solution in dry DMF (6ml).Then reactant was stirred in ice bath 2 hours, stirring at room 16 hours, water quenching and use ethyl acetate extraction then.Organic phase washes with water, uses anhydrous sodium sulfate drying, and is concentrated into dried.Residue is through flash silica gel column chromatography purification (ethyl acetate: methyl alcohol=98:2), and obtain 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-N-(2-hydroxyl-1-phenylethyl)-yellow solid (0.18g of 4-oxo butyramide; 22%; M.p.212~215 ℃) (pure diastereomer R
fSmaller).
With 2-acetylaminohydroxyphenylarsonic acid 4-(2-amino-5-chlorophenyl)-N-(2-hydroxyl-1-phenyl-ethyl)-4-oxo-butyramide (pure diastereomer R
fSmaller) (0.155g; 0.383mmol) at 2N HCl(15ml) and in solution, reflux 6 hours, to doing, residue is soluble in water, uses CH with this solution evaporation
2Cl
2Washing and revaporization, 30% ammonia soln=140:60:6), obtain (S)-(-)-2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyro-yellow solid (0.048g crude product is through flash silica gel column chromatography purification (chloroform: methyl alcohol:; 50%, m.p.205~208 ℃; [α]
20 D=-12.0 ° (1%, CH
3COOH).
According to similarity method, can prepare following compounds:
(R)-(+)-2-amino-4-(2-amino-5-chloro-phenyl-)-4-oxo-butyric acid (D-5-chloro kynurenine); [α]
20 D=+11.5 ° (1%, CH
3COOH).
Embodiment 7
Orally administered tablet
Tablet can make by known method such as direct compression process or wet granulation process.
For example, every heavy 0.250g and the tablet that contains the 50mg active substance can make as follows:
Form (10,000):
2-amino-4-(2-amino-5-chloro-phenyl-)-4-oxy butyrate 500g
Lactose 1400g
W-Gum 500g
Talcum powder 80g
Magnesium Stearate 20g
With 2-amino-4-(2-amino-5-chloro-phenyl-)-W-Gum of 4-ketobutyric acid, lactose and half amount mixes, and mixture is pressed through 0.5mm purpose sieve.W-Gum (10g) is suspended in the warm water (90ml), and the slurries of gained are used for powder is granulated, and the grain that drying is made is crossed the 1.4mm mesh sieve, adds remaining starch, talcum powder and Magnesium Stearate then, carefully mixes compressing tablet then.
The tablet of other dosage can make by the ratio of regulating active substance and assistant agent.
Embodiment 8
Orally administered capsule
Every inclusion is that 0.200g and the capsule that contains the 20mg active substance can make as follows: the composition of 500 capsules:
2-amino-4-(2-amino-5-chloro-phenyl-)-4-oxo-butyric acid 10g
Lactose 80g
W-Gum 5g
Magnesium Stearate 5g
Above-mentioned substance is packed in the biplate hardness gelatine capsule into the heavy 0.200g of the content of every capsules.
Embodiment 9
Intramuscularly agent 25mg/ml
Medicinal composition for injections can make by following method, with 2-amino-4-(2-amino-5-chlorophenyl of 25g)-4-oxo-butyro-sodium salt is dissolved in the water for injection (100ml) and makes injection liquid, be encapsulated in then in the ampoule of 1~5ml.
Claims (8)
1, as the use of a compounds of kynurenine aminotransferase (KAT) inhibitor, this compounds be used for the treatment of with old and feeble relevant knowledge knows obstacle and term brain function lack of proper care.
2, according to the use of claim 1, wherein the compound as kynurenine aminotransferase (KAT) inhibitor is the compound with logical formula I, its individual isomer or its mixture of isomers, and medicinal acceptable salt.
Wherein R is halogen, C
1-C
6Alkyl, C
5-C
7Cycloalkyl, phenyl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, phenyl C
1-C
4Alkoxyl group or trifluoromethyl;
R
1Be hydroxyl, C
1-C
6Alkoxyl group, amino, single C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, hydroxyl amino, C
1-C
4Alkoxy amino or benzyloxy amino.
3, the compound of formula (IA), its individual isomer or its mixture of isomers, and medicinal acceptable salt,
Wherein R is halogen, C
1-C
6Alkyl, C
5-C
7Cycloalkyl, phenyl-C
1-C
4Alkyl, C
1-C
6Alkoxyl group, C
6-C
10Aryloxy, phenyl C
1-C
4Alkoxyl group or trifluoromethyl;
R
1Be hydroxyl, C
1-C
6Alkoxyl group, amino, single C
1-C
6Alkylamino, two-C
1-C
6Alkylamino, hydroxyl amino, C
1-C
4Alkoxy amino or benzyloxy amino,
Condition is:
(ⅰ) work as R
1Be that then this halogen was not a fluorine when hydroxyl and while, R was halogen;
(ⅱ) work as R
1Be that hydroxyl and while R are C
1-C
6During alkyl, this C then
1-C
6Alkyl is not a methyl.
4, according to the compound of the general formula (IA) of claim 3, its individual isomer or its mixture of isomers, and medicinal acceptable salt,
Wherein R is a halogen, C
1-C
6Alkyl or C
5-C
7Cycloalkyl;
R
1Be hydroxyl,
Condition is:
(ⅰ) when R is halogen, then this halogen is a fluorine not;
(ⅱ) when R be C
1-C
6During alkyl, this C then
1-C
6Alkyl is not a methyl.
5, be selected from following compound, its individual isomer or its mixture of isomers, and medicinal acceptable salt:
2-amino-4-(2-amino-5-chlorophenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-ethylphenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-bromo phenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-n-propyl phenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-isopropyl phenyl)-4-oxo-butyric acid;
2-amino-4-(2-amino-5-cyclohexyl phenyl)-4-oxo-butyric acid.
6, the compound of defined formula I compound of a kind of preparation claim 2 or the defined formula of claim 3 (IA), or the method for its medicinal acceptable salt, this method comprises:
1) makes the compound of formula II and chloro acetonitrile reaction and obtain the compound of formula III
Wherein R in the claim 2 in formula I or claim 3 Chinese style (IA) definition,
Wherein the R definition as above.
2) make the sodium salt reaction of the compound and the kharophen propanedioic acid of formula III, and generate the compound of formula IV
Wherein the R definition as above.
3) the formula IV compound of above-mentioned definition is handled with concentrated hydrochloric acid, generated formula I or compound (IA), wherein R defines as above, R
1Be hydroxyl, and if desired, can change into R to formula I or compound (IA)
1Part is not (I) of hydroxyl or other compound (IA); And if desired, can be with formula I or the different conversion salify of compound (IA), and if desired, can with formula I or (IA) isomer mixture of compound be separated into single isomer.
7, a kind of medicinal compositions, said composition contain the formula I compound of the claim 2 for the treatment of significant quantity or according to the compound of the formula (IA) of claim 3, or its medicinal acceptable salt, and medicinal acceptable carrier, thinner or vehicle.
8, according to the medicinal compositions of claim 7, it is used for the treatment of old and feeble relevant knowledge and knows obstacle and brain function imbalance in term.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US08/102,843 US5519055A (en) | 1993-08-06 | 1993-08-06 | Substituted kynurenines and process for their preparation |
US08/102,843 | 1993-08-06 |
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Family
ID=22291962
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US (2) | US5519055A (en) |
EP (2) | EP0919538A1 (en) |
JP (1) | JPH08502523A (en) |
CN (1) | CN1113386A (en) |
AT (1) | ATE181728T1 (en) |
AU (1) | AU680672B2 (en) |
CA (1) | CA2145178A1 (en) |
DE (1) | DE69419306D1 (en) |
FI (1) | FI951631A (en) |
HU (1) | HUT70394A (en) |
IL (1) | IL110563A (en) |
PL (1) | PL308237A1 (en) |
TW (1) | TW408099B (en) |
WO (1) | WO1995004714A1 (en) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1330774C (en) * | 2002-03-01 | 2007-08-08 | 国家人类基因组南方研究中心 | Kynurenine hydrolase polymorphism and its diagnostic use |
CN103228660A (en) * | 2010-12-01 | 2013-07-31 | 辉瑞大药厂 | Kat II inhibitors |
Families Citing this family (10)
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GB9521486D0 (en) * | 1995-10-20 | 1995-12-20 | Pharmacia Spa | Fluoro-substituted benzoylpropionic acid derivatives |
GB9522617D0 (en) * | 1995-11-03 | 1996-01-03 | Pharmacia Spa | 4-Phenyl-4-oxo-butenoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity |
GB9522615D0 (en) | 1995-11-03 | 1996-01-03 | Pharmacia Spa | 4-Phenyl-4-oxo-butanoic acid derivatives with kynurenine-3-hydroxylase inhibiting activity |
GB9618349D0 (en) * | 1996-09-03 | 1996-10-16 | Pharmacia Spa | N-substituted 2-amino-4-phenyl-4-oxo-butanoic acid derivatives with kynurenine-3-hydroxylase inhibitory activity |
GB9725055D0 (en) * | 1997-11-26 | 1998-01-28 | Pharmacia & Upjohn Spa | 1,3,4-thiadiazoles compounds |
ITMI20041626A1 (en) * | 2004-08-06 | 2004-11-06 | Roberto Pellicciari | QUINURENIN-AMINO-TRANSFERASE INHIBITORS |
WO2007064784A1 (en) * | 2005-11-30 | 2007-06-07 | The University Of Maryland, Baltimore | Inhibitors of kynurenine aminotransferase and uses therefor |
US9834801B2 (en) | 2013-03-14 | 2017-12-05 | Vistagen Therapeutics, Inc. | Methods for the synthesis of chiral kynurenine compounds |
CA2946702C (en) * | 2014-04-23 | 2022-06-28 | Mitsubishi Tanabe Pharma Corporation | Bicyclic or tricyclic heterocyclic compound |
US10793582B2 (en) | 2015-10-22 | 2020-10-06 | Mitsubishi Tanabe Pharma Corporation | Bicyclic heterocyclic compound |
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ATE168989T1 (en) * | 1991-02-28 | 1998-08-15 | Merrell Pharma Inc | NMDA ANTAGONISTS |
US5495044A (en) * | 1991-04-18 | 1996-02-27 | University Of Georgia Research Foundation, Inc. | Inhibitors of kynureninase |
JPH06510023A (en) * | 1991-04-18 | 1994-11-10 | ユニバーシティ オブ ジョージア リサーチ ファウンデーション,インコーポレイテッド | Inhibitors of kynureninase |
IT1265101B1 (en) * | 1993-07-23 | 1996-10-30 | Erba Carlo Spa | DERIVATIVES OF 2-AMINO-4-PHENYL-4-BUTYRIC BONE ACID |
-
1993
- 1993-08-06 US US08/102,843 patent/US5519055A/en not_active Expired - Fee Related
-
1994
- 1994-07-15 DE DE69419306T patent/DE69419306D1/en not_active Expired - Lifetime
- 1994-07-15 HU HU9500997A patent/HUT70394A/en unknown
- 1994-07-15 PL PL94308237A patent/PL308237A1/en unknown
- 1994-07-15 CA CA002145178A patent/CA2145178A1/en not_active Abandoned
- 1994-07-15 CN CN94190583A patent/CN1113386A/en active Pending
- 1994-07-15 EP EP98122053A patent/EP0919538A1/en not_active Withdrawn
- 1994-07-15 AT AT94922532T patent/ATE181728T1/en not_active IP Right Cessation
- 1994-07-15 JP JP7506414A patent/JPH08502523A/en active Pending
- 1994-07-15 WO PCT/US1994/007804 patent/WO1995004714A1/en active IP Right Grant
- 1994-07-15 EP EP94922532A patent/EP0663899B1/en not_active Expired - Lifetime
- 1994-07-15 AU AU73602/94A patent/AU680672B2/en not_active Ceased
- 1994-07-20 TW TW083106650A patent/TW408099B/en active
- 1994-08-04 ZA ZA945830A patent/ZA945830B/en unknown
- 1994-08-04 IL IL11056394A patent/IL110563A/en not_active IP Right Cessation
-
1995
- 1995-04-05 FI FI951631A patent/FI951631A/en unknown
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1330774C (en) * | 2002-03-01 | 2007-08-08 | 国家人类基因组南方研究中心 | Kynurenine hydrolase polymorphism and its diagnostic use |
CN103228660A (en) * | 2010-12-01 | 2013-07-31 | 辉瑞大药厂 | Kat II inhibitors |
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Publication number | Publication date |
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PL308237A1 (en) | 1995-07-24 |
AU680672B2 (en) | 1997-08-07 |
AU7360294A (en) | 1995-02-28 |
US5708030A (en) | 1998-01-13 |
CA2145178A1 (en) | 1995-02-16 |
FI951631A0 (en) | 1995-04-05 |
ZA945830B (en) | 1995-03-09 |
HUT70394A (en) | 1995-10-30 |
EP0663899B1 (en) | 1999-06-30 |
WO1995004714A1 (en) | 1995-02-16 |
TW408099B (en) | 2000-10-11 |
IL110563A0 (en) | 1994-11-11 |
DE69419306D1 (en) | 1999-08-05 |
EP0663899A4 (en) | 1996-01-17 |
HU9500997D0 (en) | 1995-06-28 |
EP0663899A1 (en) | 1995-07-26 |
ATE181728T1 (en) | 1999-07-15 |
IL110563A (en) | 1999-04-11 |
JPH08502523A (en) | 1996-03-19 |
EP0919538A1 (en) | 1999-06-02 |
US5519055A (en) | 1996-05-21 |
FI951631A (en) | 1995-04-05 |
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